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Diastolic Dysfunction with Vascular Deficits in HIV-1-Infected Female Humanized Mice Treated with Antiretroviral Drugs
Get PDFEarly-onset heart failure is a major treat to healthy aging individuals with HIV-1 infection. Women with HIV-1 infection (WLWH) are especially vulnerable and develop heart failure with preserved ejection fraction (HFpEF), of which left ventricular diastolic dysfunction, vascular deficits, myocardial infarction, and fibrosis are major components. HIV-infected rodent models that exhibit these pathophysiological features remain under-reported, and this has left a void in our understanding of their molecular causes and therapeutic strategies to blunt its development. Here, we show that female NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ humanized mice (Hu-mice) infected with HIV-1ADA and treated for 13 weeks with dolutegravir (DTG)/tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) develop progressive diastolic dysfunction with preserved ejection fraction (E:A ratio, E:e\u27, IVRT, left atrial volume and global longitudinal strain increased by 32.1 ± 5.1%, 28.2 ± 5.6%, 100.2 ± 12.6%, 26.6 ± 4.2% and 32.5 ± 4.3%, respectively). In vivo photoacoustic imaging revealed a 30.4 ± 6.8% reduction in saturated oxygenated hemoglobin in the anterior wall of the heart. The ex vivo analysis of hearts showed a reduction in density of perfused microvessels/ischemia (30.6 ± 6.2%) with fibrosis (20.2 ± 1.2%). The HIF-1α level was increased 2.6 ± 0.5-fold, while inflammation-induced serum semicarbazide amine oxidase and glycolysis byproduct methylglyoxal increased 2-fold and 2.1-fold, respectively. Treating H9C2 cardiac myocytes with DTG, FTC and TDF dose-dependently increased expression of HIF-1α. These data show that HIV-infected Hu-mice treated with DTG/TDF/FTC for thirteen weeks develop cardiac diastolic dysfunction, with vascular deficits, ischemia, and fibrosis like those reported in women living with HIV-1 infection (WLWH). They also show that DTG, TDF, and FTC treatment can increase total HIF-1α in H9C2 cell
The Effect of Pitch Clock Rules on Pitching Injuries In MiLB From 2012 to 2024
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Search Strategies for Malondialdehyde-Acetaldehyde Modified Macromolecules and Resulting Autoantibodies in Rheumatoid Arthritis Pathogenesis: A Systematic Literature Review
Get PDFDesign and Synthesis of FDI-6-Based Hydrophobic Tag Degraders Targeting FOXM1
Get PDFForkhead box M1 (FOXM1) is a transcription factor overexpressed in numerous human cancers, and this is often associated with a poor prognosis. FOXM1 regulates transcription by binding to target gene promoters and interacts with key oncogenic pathways. Previously, small molecule inhibitors have been used to target FOXM1 by disrupting DNA binding, with FDI-6 being the first selective inhibitor reported. However, FOXM1 has functions besides DNA binding, indicating the need for an alternate targeting approach to eliminate FOXM1. Targeted protein degradation, including PROTACs and HyT degraders, has emerged as a viable approach to degrade target proteins. An FDI-6-based PROTAC for FOXM1 has been reported, leading us to hypothesize that an FDI-6-based HyT degrader could also regulate FOXM1 levels. By replacing the cereblon ligand in the PROTAC with a hydrophobic group, we aim to reduce off-target effects and increase specificity for FOXM1. HyT degraders bind to the surface of target proteins, exposing hydrophobic regions that can mimic the characteristics of misfolded proteins, which in turn triggers the protein quality control system to induce proteasomal degradation. To test our hypothesis, we designed and synthesized eight FDI-6-based HyT degraders using norbornene and adamantane as the hydrophobic groups. These degraders were purified by flash chromatography and characterized by 1H and 13C NMR spectroscopy. Their final purity (\u3e95%) was confirmed using high-performance liquid chromatography (HPLC). Compound 6a was tested against OVCAR4 ovarian cancer cells. Target engagement studies showed a decrease in FOXM1 protein levels, suggesting that HyT degraders may be a promising approach for degrading FOXM1
The Alcohol Exposome
Get PDFScience is now in a new era of exposome research that strives to build a more all-inclusive, panoramic view in the quest for answers; this is especially true in the field of toxicology. Alcohol exposure researchers have been examining the multivariate co-exposures that may either exacerbate or initiate alcohol-related tissue/organ injuries. This manuscript presents selected key variables that represent the Alcohol Exposome. The primary variables that make up the Alcohol Exposome can include comorbidities such as cigarettes, poor diet, occupational hazards, environmental hazards, infectious agents, and aging. In addition to representing multiple factors, the Alcohol Exposome examines the various types of intercellular communications that are carried from one organ system to another and may greatly impact the types of injuries and metabolites caused by alcohol exposure. The intent of defining the Alcohol Exposome is to bring the newly expanded definition of Exposomics, meaning the study of the exposome, to the field of alcohol research and to emphasize the need for examining research results in a non-isolated environment representing a more relevant manner in which all human physiology exists
Enhancing Learning Through Role-Play in a Low-Fidelity Disaster Simulation
Get PDFABSTRACT
Background: This report shares a best practice approach to low-fidelity simulation as a pedagogical method in disaster triage training for undergraduate nursing students.
Methods: This study utilized multi-year quantitative data such as student age, gender, GPA, prior simulation experience, and self-reported confidence in the START Triage application. It also utilized a secondary qualitative analysis of the debriefing process.
Results: Students who participated in a simulation event playing the role of a disaster victim scored significantly higher on subsequent performance as TRIAGE practitioners than students without roleplay experience. Perhaps even more compelling, these learning outcomes were demonstrated 18 months after the role-play experience.
Conclusion: Planned, coordinated low-fidelity simulation learning experiences are beneficial in nursing student instruction. This report proposes a cost-effective teaching strategy that utilizes low-fidelity simulation by incorporating role-play to enhance student learning.
KEYWORDS: simulation learning, triage, disaster response, health professions, experiential learning
Key Messages and Terms Students who experience triage as a simulated patient, perform exponentially better on subsequent experience as a practitioner. Patient simulation using students is an inexpensive, safe teaching methodology with impressive knowledge retention (18 months) results in keeping with experiential learning theory
